Term
| What are the primary targets of Scleroderma? |
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Definition
Chronic, immune-mediated inflammation and fibrosis in
1) Blood Vessels
2) Interstitial tissues in GI, lung, heart and kidney |
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Term
| What epidemiological characteristics define Scleroderma? |
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Definition
1) US incidence (20 cases/million), prevalence (240 cases/million)
2) 3:1 f:M
3) 4:3 African American: Caucasian
4) most common b/w 45-64 |
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Term
| What are some features to look for in first-degree relatives which might suggest a risk for Schleroderma in a patient? |
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Definition
Autoimmune background diseases
1) RA
2) SLE
3) Thyroid disease |
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Term
| What candidate genes have been identified to be associated with Schleroderma devlopment? |
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Definition
STAT4, IRF5 and HLA/MHC class II confirmed by GWAS
1) STAT4- promotes Th1 cell development and (-) regulator of Th2. (SLE and RA)
2) IRF5- t-factor for IFN activation (SLE)
3) HLA class II- multiple haplotypes
4) TNFSF4- encodes OX40L, which is expressed on DC, endothelial cells and B cells to co-stimulate T cells
5) BANK1: B cella adaptor protein linking BCR to down stream signalling (SLE and RA)
6) TBX21- Th1 t-factor, T-bet, important for Th1 development |
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Term
| How can you classify Systemic Sclerosis? |
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Definition
1) Diffuse cutaneous involvement- early visceral disease (lung, heart, kidney) and diffuse skin thickening, affecting the knees and elbows
2) Limited cutaneous involvement- late visceral disease (pulm hypertension) with restricted, non-progressieve thickening (distal extremities)
3) Overlap- features of other connective tissue diseases (IIM>SLE>RA) |
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Term
| What are the two major types of Scleroderma? |
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Definition
1) Localized (Morphea or Linear)
2) Systemic (diffuse cutaneous, limited cutaneous or overlap) |
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Term
A patients serum contains anti-U1RNP antibodies. Which subset of systemic sclerosis might you diagnose?
What about if SCL-70 and anti-RNA poli III showed up? |
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Definition
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Term
| A patients serum contains anti-centromeric and anti-Th-To antibodies. Which subset of systemic sclerosis might you diagnose? |
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Definition
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Term
| Describe the most common features of organ system involvement in Scleroderma |
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Definition
1) Skin- thickening/hardening
2) Peripheral vascular- Raynauds' phenomenon (pitting scars and ulcers)
3) Joint/Tendons- stiffness/pain/contracture (NO proliferative synovitis as in RA)
4) Skel Muscle- proximal weakness, minimal CK elevation (noninflammatory myopathy)
5) GI-
Esophageal dysmotility causing reflux
SI leading to abdominal distention/bloating, diarrhea, weight loss nad malnutrition
6) Interstitial lung disease (slowly progressive dyspnea on exertion and basilar fibrosis on CT)
7) Pulmonary Arterial Hypertension (rapidly progressive dyspnea on exertion)
8) Cardiac- arrhythmia (fibrosis), diastolic dysfunction (fibrosis) and systolic dysfunction (myopathy-rare)
9) Renal- "crisis" with severe systemic hypertension (thrombocytopenia and microangiopathic hemolytic anemia and renal failure-monitor with BP) |
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Term
| How could you distinguish between Diffuse Cutaneous and Limited Cutaneous forms of System Scleroderma in terms of their organ system distributions? |
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Definition
Summary:
1) Look for Pulmonary Hypertension and Esophageal issues in Limited cases. They should present more slowly with limited skin involvement and slowly accumulating organ damage.
2) Look for severe fibrosis, myocardial issues, renal crisis and esophageal issues in diffuse case. You should observe early organ involvement and rapid involvement of the skin.
Long
1) both with show GI issues in the esophagus (75%) and malabsorption (5% in limited vs. 2% in diffuse)
2) 20-25% of limited cases will show pulmonary hypertension (<1 % in diffuse)
3) 15% of diffuse cases will show severe fibrosis (only 5% in limited)
4) 5-10% of diffuse cases show Myocardial issues (1% in limited)
5) 15-20% of diffuse cases show renal crisis (<1% of limited) |
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Term
| What are the 3 clear components of Scleroderma pathogenesis? |
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Definition
1) Vascular injury
2) Fibrosis with overproduction of collagen and connective tissue matrix
3) Immune system activation |
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Term
| What animal models of SSc are available? |
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Definition
All of imperfect
1) Induced- chemical exposure (biomycin), fibrogenic GF (TGF-b), and GVH reaction
2) Genetic- "Scleroderma chicken,"
"tight skin" mice- Tsk1 mutatns (fibrillin-1 gene, resulting in duplication, causing collagen accumulation without inflammation
3) Transgenics |
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Term
| What Vascular/Endothelia changes underly Scc? |
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Definition
Endothelial Cell (EC) dysfunction due to injury
1) Endothelin-1 (ET-1) levels increase (constriction and fibrogenic) affecting vascular tone
2) Defective vasculogenesis- lack of precursors (EPCs) in SSc pts and inability to differentiate
3) Up-regulation of adhesion molecules, leukocyte adhesion and leukocyte migration |
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Term
| What Immunological changes underly Scc? |
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Definition
Autoantibodies, T-cell activation, Macrophages
1) Autoantibodies
9 diagnostic (not linked to pathogenesis)
Anti-fibroblast (maybe mediated by anti-topoisomerase antibodies)
Autoantibodies against auto-reactive T-cells.
2) T-cell activation- Th2 cytokine-predominant response, which promotes fibrosis (TGF-b, IL-4, IL-1) and activates monocytes.
3) Monocytes/macrophages- antigen presentation to T-cells and source of cytokines and MMPs |
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Term
| Which cytokines are increased in the serum in Scc and why are they relevant? |
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Definition
| 1) IL-1, IL-2, IL-2R, IL-4, IL-8, IL-17, TNF-a, IFN produced by macrophages/monocytes, T-cells, fibroblasts and EC cells |
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Term
| What organ is useful in crossing off SSc from a differential? |
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Definition
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Term
| Which antibodies used in clincal-serological classification of systemic sclerosis are most commonly found in the US? |
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Definition
1) Anti SCL-70 (topoisomerase)(diffuse)
2) Anti-RNA Poli III (diffuse)
3) Anti-centromere (limited) |
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Term
| How can you most easily identify Raynauds to determine peripheral vasacular involvement? |
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Definition
| Look at capillaries under nail-fold microscopy |
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Term
True or False:
You should look for proliferative synovitis if you suspect SSc? |
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Definition
FALSE!
You see fibrous synovitis, but not profilerative, inflammatory synovitis (this would be RA) |
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Term
| What should you look for on a skin biopsy to diagnose SSc? |
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Definition
| Disorganized collagen deposition |
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Term
| What is the proposed relationship between SCL-70 and Scc? |
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Definition
| This is a diagnostic antibody for diffuse, systemic Sc, but is also thought to mediate fibroblast activity (pathogenesis). |
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Term
| Which 3 features of the immune system are activated in SSc? |
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Definition
1) Auto-antibodies (SCL-70, RNA poli III and anti-centromere are key)
2) T-cells (Th2 dominant)
3) Monocytes/Macrophages for APC, cytokines and MMPs |
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Term
| What is a major difference between the immune response seen in SSc and that seen in GAP? |
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Definition
| SSc is dominated by Th2, while GAP is dominated by Th1 (remember, PR3 activates DCs which leads to IL-18 release in LN) |
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Term
| Where are the cytokines seen in SSc produced? |
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Definition
Endothelial cells and Fibroblasts (as well as macrophages).
Autocrine loops of cytokine release may be involved in pathogenesis. |
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